Project Summary/Abstract 29 million Americans suffer from Type 2 Diabetes Mellitus (T2DM) and 84.1 million pre-diabetics risk becoming diabetic There is need for treatments providing improved efficacy, durability and that is customized to patient?s compliance. Neuromodulation of nerves innervating organ systems that regulate plasma glucose (PG) may be a method for treating T2DM. Standalone stimulation or ligation of the vagus nerve has undesirable results. Little is known; however, of the effect on PG with combined dual neuromodulation consisting of adjustable pacing simulation of fibers innervating the pancreas (increasing insulin secretion) with simultaneous adjustable and reversible electrical blockade of neuronal fibers innervating the liver (preventing glucose release) in a T2DM animal model . We used a proprietary bio-electronic device and algorithm developed by Enteromedics Inc. comprising a pacing stimulation (1 Hz) of the celiac branch of the vagus nerve (innervating the pancreas) with a simultaneous reversible high frequency alternating current (HFAC)-induced blockade of the hepatic branch (innervating the liver). This technology is termed Diabetes Blocking-Stimulation Neuromodulation (DBSN). Experiments were conducted in T2DM Zucker rats and a pig model of T2DM. We measured PG following an IV or oral glucose tolerance (OGTT) test with DBSN. In a T2DM pig model chronic study when subjected to DBSN blood glucose was significantly decreased following an OGTT compared to Sham (DBSN=2066388 area units (AU) vs Sham=3935267 AU) analyzing the area under the curve. In a T2DM rat study a similar and significant result was observed with DBSN (89868 AU) compared to Sham (1543257 AU). There was no significant difference from Sham compared to Vagotomy or Stimulation alone. Much was learned with these studies; however, there is still important information that needs to be gathered. First would be to investigate if delivery of DBSN at time points following an OGTT will still be affective at increasing glycemic control. Second we need to investigate if a multiplex algorithm would be affective at increasing glycemic control. Finally the safety of DBSN needs to be tested by histology of organs that the celiac and hepatic branch innervate